Immune System

Encyclopedia of Aging
COPYRIGHT 2002 The Gale Group Inc.

IMMUNE SYSTEM

The immune system provides the body with resistance to disease. Innate immunity is furnished by relatively nonspecific mechanisms, such as the rapid inflammation experienced shortly after injury or infection. In contrast to innate mechanisms that hinder the entrance and initial spread of disease, adaptive immunity is more selective in its activity, and upon repeated exposures to pathogens can often prevent disease. There are two kinds of adaptive immune responses. Humoral immune responses are effective against agents that act outside of cells, such as bacteria and toxins. During humoral immune responses, proteins called antibodies, which can bind to and destroy pathogens, are secreted into the blood and other body fluids. In contrast, cell-mediated immune responses are important in resisting diseases caused by pathogens that live within cells, such as viruses. During cell-mediated responses, immune cells that can destroy infected host cells become active. Furthermore, cell-mediated immunity may also destroy cells making aberrant forms or amounts of normal molecules, as in some cancers.

Numerous aspects of adaptive immunity differ substantially in aged individuals from what is seen in young adults. For example, aged individuals often have attenuated or otherwise impaired immune responses to various bacterial and viral pathogens. Indeed, this general trend forms the basis for recommended immunizations against infectious agents that younger individuals resist easily. Aged individuals often respond differently to vaccination, however, sometimes resulting in a lack of protective immunity. In addition, unto-ward immune phenomena, such as certain forms of autoimmunity, as well as cancers involving cells of the immune system, show increased incidence in aged individuals. A complete understanding of these age-associated changes in immune status and function remains elusive, requiring knowledge of the mechanisms underlying maintenance, activation, and control of the immune system.

Lymphocytes, clonal selection, and antigen recognition

Lymphocytes are central to all adaptive immune responses. They originate from stem cells in the bone marrow. Cells destined to become lymphocytes either mature in the bone marrow or exit the marrow and mature in the thymus (because they are sites of lymphocyte production, the bone marrow and thymus are termed the primary lymphoid organs ). Lymphocytes that mature in the bone marrow make antibodies and are called B lymphocytes (B cells); whereas lymphocytes that mature in the thymus are called T lymphocytes (T cells). The T lymphocytes are further subdivided into functional subsets: cytotoxic T lymphocytes (Tc cells) generate cell-mediated immune responses and can destroy other cells that have pieces of antigen on their surface; helper T lymphocytes (Th cells) regulate the immune system, governing the quality and strength of all immune responses. Tc and Th cells are often termed CD8+ and CD4+ T cells, based on so-called "cluster designation" (CD) molecules found on their surface.

The notion that specificity in adaptive immune responses derives from a clonal distribution of antigen receptors, coupled with requisite receptor ligation for activation, is the central argument of the generally accepted clonal selection hypothesis. Simply put, while billions of different antigen receptors can be made (in terms of antigen-binding specificity), each lymphocyte makes only one kind. Engagement of this receptor is requisite for lymphocyte activation, so a given antigen activates only those lymphocytes whose receptors bind well, yielding appropriate specificity in the overall response.

Antigen recognition by lymphocytes. The B lymphocyte's antigen receptor is a membrane-bound version of the antibody it will secrete if activated. When activated, a B lymphocyte's secreted antibodies enter the blood and other body fluids, where the bind the antigen and help destroy it. In contrast, a T lymphocyte's antigen receptor (TcR) is not secreted, but instead binds antigen displayed on the surface of other cells. Further, while B lymphocytes can bind native antigens directly, T lymphocytes can only bind an antigen when it is degraded and presented. Antigen presentation occurs when degradation products
of protein antigens become attached to molecules encoded by a group of genes called the Major Histocompatibility Complex (MHC) and displayed on cell surfaces. All vertebrates have a homologue of this gene complex; for example, the human MHC is named HLA. When proteins either are made within a cell or are ingested by phagocytosis, they may be degraded by a variety of systems. The resulting small peptides become associated with binding clefts in MHC molecules. This peptide-MHC molecule combination is then displayed on the cell's surface for recognition by T lymphocytes. Different categories of MHC molecules exist, encoded by different genes within the MHC. Class I MHC molecules tend to become associated with the degradation products of proteins that were synthesized inside the cell. Further, class I molecules generally present antigen to cytotoxic T cells, so if a cell makes class I MHC molecules, it can present antigen to cytotoxic T cells. Most kinds of cells in the body express MHC class I molecules, so nearly any cell that is synthesizing nonself proteins (such as those from a viral infection) can be destroyed by cytotoxic T cells. In contrast, class II MHC molecules present antigen to helper T cells, so a cell that makes class II MHC molecules can present antigen to helper T cells. Only a few kinds of cells, including dendritic cells, macrophages, and B lymphocytes, normally express class II MHC molecules and present antigen to Th cells.

Lymphocyte development, production, and receptor diversity. Since antigen receptor specificities are clonally distributed, the selectivity of immune responses relies on the constant availability of a large and diverse pre-immune lymphocyte pool. Towards this end, millions of lymphocytes are produced daily in the marrow and thymus. As lymphocytes develop and mature, they begin to express their surface-bound antigen receptor. The receptor's expression and specificity are established through a series of DNA rearrangement and splicing events that yield functional antigen receptor genes. Because the portion of the receptor molecule that will interact with antigen derives from such pseudorandom gene-splicing mechanisms, the number of permutations available to afford diversity among clonally distributed antigen-combining sites is enormous—in the range of 1012.

Age-associated changes in lymphocyte development and selection. Lymphocyte production and selection changes with age. For example, the rate at which lymphocytes are generated in the thymus and bone marrow, which will dictate the turnover of mature lymphocytes in the periphery, has been shown to decrease with age. These shifts appear to reflect a combination of factors, which may include a lower frequency of successful antigen-receptor-gene expression, reflecting intrinsic changes in B cell progenitors. Further, failure or diminution of stromal trophic elements necessary for the survival of developing lymphocytes may occur with increasing age. Finally, shifts in the representation of various differentiation subsets, likely reflecting changes in the homeostatic processes that govern steady state numbers, shift with age.The mechanistic bases for these changes remain unclear, and are the subject of intense investigation.

In addition to changes in lymphocyte production, the degree of receptor diversity within both mature and developing lymphoid compartments may become truncated with age. This may alter the frequency or breadth of available primary clones that can engage in immune responses, affecting the outcome of immunization or vaccination. Similar to the factors contributing to reduced production rates, the basis for truncated antigen receptor diversity appears manifold. For example, it likely involves downstream effects precipitated by altered lymphocyte production and selection; but probably also originates from the life-long accumulation of expanded memory clones, which are the result of antigen-driven expansion, and perforce less diverse.

Secondary lymphoid organs and immune responses

Lymphoid organs, vessels, and recirculation. Mature lymphocytes constantly travel through the blood to the lymphoid organs and then back to the blood. This constant recirculation insures that the body is continuously monitored for invading substances. The major areas of antigen contact and lymphocyte activation are the secondary lymphoid organs. These include the lymph nodes, spleen, and tonsils, as well as specialized areas of the intestine and lungs. Appropriate recirculation and compartmentalization is essential to vigorous immune function, since this provides appropriate surveillance of the host for antigens, as well as the appropriate juxtaposition of all cellular elements to insure fruitful interaction.

Cell interactions in immune responses. Although antigen binding is necessary to activate
a B or T cell, that alone is insufficient to induce an immune response. Instead, both humoral and cell-mediated responses require interactions between three cell types: antigen-presenting cells (APCs), Th cells, and either a B cell or Tc cell. Generally, the interaction between the APC and Th cells involves not only the binding of the TcR by the antigenic peptides in association with the MHC, but a series of second signals. These requisite second signals are afforded by the interactions of both membrane-bound ligand receptor pairs, known collectively as costimulators, as well as a variety of soluble growth and differentiation factors secreted by the antigen-presenting cells.

Humoral immune responses involve several events following the entry of antigen. First, antigen-presenting cells take up some of the antigen, attach pieces of it to Class II MHC molecules, and present it to T-helper cells. Binding the presented antigen activates T-helper cells, which then divide and secrete stimulatory molecules called interleukins. These stimulatory molecules in turn activate any B lymphocytes that have bound the antigen, and these activated B cells then divide, differentiate, and secrete antibody. Finally, the secreted antibodies bind the antigen and help destroy it through a variety of so-called effector mechanisms, including neutralization, complement fixation, and opsonization.

Cell-mediated immune responses involve several events following the entry of antigen. Helper T cells are required, so some of the antigen must be taken up by APCs and presented to T-helper cells. Binding the presented antigen activates the T-helper cells to divide and secrete interleukins. These in turn activate any cytotoxic T cells that have bound pieces of the antigen presented by class I MHC molecules on infected cells. The activated cytotoxic cells can then serially kill cells displaying antigen presented by class I MHC molecules, effectively eliminating any cells infected with the antigen.

Age-associated changes in recirculation, interaction, and immune responses. The patterns of compartmentalization and recirculation may vary with age, and again likely reflect a combination of factors. These probably include relative increases in memory-cell populations, whose recirculation and compartmentalization properties differ from primary lymphocytes, as well as alterations in the efficacy and structure of the lymphatics caused by either intrinsic or extrinsic factors. Of course, these shifts may alter the handling and recognition of antigens by APCs and lymphocytes, consequently impacting heavily on all negative and positive selective processes. It is also clear that the strength and duration of immune responses can change with age. Most reports of such changes are largely descriptive and subject to great variability.

How cells bearing potentially autoreactive receptors are controlled remains an area of intense investigation, but several mechanisms clearly play important roles. Many autoreactive clones are eliminated before they mature in the marrow and thymus, because when immature B or T cells have their antigen receptor occupied they undergo deletion via apoptotic cell death. In contrast, mature lymphocytes resist death induced via receptor ligation. Regardless of the exact mechanisms involved, these so-called central deletion mechanism provide a means to screen and eliminate incipient autoreactive cells before they completely mature. However, these central tolerance mechanisms, while clearly an important element of immunologic tolerance, are insufficient to fully explain the lack of auto-reactivity. For example, some self molecules are expressed only in tissues found outside of the thymus or bone marrow, precluding exposure of developing lymphocytes. Thus, a variety of peripheral tolerance mechanisms are believed to be important in successful avoidance of self reactivity. These include the functional inactivation of lymphocytes through anergy, the blockage or prevention of appropriate second signals, discussed above, and the sequestration of certain self components in areas where lymphocytes do not recirculate, such as the chamber of the eye.

If the immune system fails to appropriately eliminate or control self-reactive cells, they may cause life-threatening autoimmune disease. These diseases may involve cell-mediated responses, humoral responses, or both. Examples of autoimmunity include: type I diabetes, where individuals make an immune response against their insulin-producing cells, destroying them and resulting in abnormal sugar metabolism; myasthenia gravis, where one makes antibodies against normal molecules that control neuromuscular activity, resulting in weakness and paralysis; and systemic lupus erythematosus, where antibodies to many normal body constituents are made, resulting in widespread symptoms. Some autoimmune diseases lead to the deposition of antibody-antigen aggregates called immune complexes in the kidney, lungs, or joints. Because these complexes will trigger complement and other inflammatory processes, they can result in severe damage to the affected areas.

Age-associated changes involving immune tolerance. Age-associated changes in the susceptibility to autoimmune phenomena are well-established. Indeed, epidemiological evidence shows that the incidence of various autoimmune diseases peaks at certain ages. Thus, while many other risk factors are also involved, elucidating the links between various autoimmune syndromes and age forms an important immunologic problem. Because the mechanisms that mediate immune tolerance per se are poorly understood, it is even more difficult to establish how age-associated factors can influence susceptibility. Clearly, shifts in the production, selection, and homeostatic processes that govern lymphocyte activity may play a role, but causal relationships await further research.

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Immune System Regulation and Nutrients

Encyclopedia of Food and Culture
COPYRIGHT 2003 The Gale Group Inc.

IMMUNE SYSTEM REGULATION AND NUTRIENTS

IMMUNE SYSTEM REGULATION AND NUTRIENTS. Chicken soup, herbal tea, and vitamin C pills take on special meaning in cold and flu season. But beyond their possible role in treatment and comfort, nutrients are essential and fundamental parts of immune system function. To understand nutrient-immune interactions, it is helpful to understand how the body's immune system functions in general.

The human immune system has evolved to the state where it cannot only maintain continual vigilance against new challenges, but can "learn" from past challenges and "remember" more efficient means of resolving those challenges if they are ever encountered again. The numerous cooperative mechanisms by which the immune system addresses (but does not "remember") novel challenges are collectively termed "innate immunity." These mechanisms include proteins that can bind to or neutralize a wide variety of foreign particles, and cells that can phagocitize foreign particles to remove them from the body. In the process of neutralizing and removing foreign particles, other cells within the immune system (mainly dendritic cells) transport samples of the foreign particles (antigens) to specialized tissues and organs (spleen, lymph nodes, Peyer's patches) where naive cells (T cells and B cells) not previously exposed to foreign particles can adapt their surface molecules (through gene recombination) in order to increase the efficiency with which later encounters with the foreign particle can be
resolved. These adapted cells and associated specialized proteins (immunoglobulins—proteins that function as antibodies) provide immunological memory of past encounters and form what is termed "acquired immunity."

The body's ability to resolve infections can be likened to the running of a race. The infectious agent must elude detection by the immune system until it can proliferate and establish itself within the body. The earlier the body can detect this infection (by maintaining a critical concentration of innate immune system cells and proteins throughout the body) and the faster the body can produce new protective cells and proteins, the better the chance of winning the race. The key steps in this process—efficient communication and rapid biosynthesis—are constrained by the availability of raw material, and in the body, raw material means nutrients. In this light, well-established nutritional principles can also be regarded as immunological paradigms.

Biosynthesis: Building New Cells and Proteins

The immune system is continually producing a remarkable number of new cells and proteins to provide a broad repertoire of potential immune responses and maintain functional concentrations in the periphery. An average adult has nearly six pounds of bone marrow, which produces about one trillion white blood cells per day, accounting for 8 percent or more of the total protein synthesis in the body. About 60 percent of bone-marrow biosynthesis is devoted to producing neutrophils (innate immune system phagocytes), amounting to about 100 billion cells a day, which then survive only one to two days in circulation. Studies in laboratory rats indicate that in the acquired immune system, cell turnover is ten times higher in the thymus than in the liver. Of the millions of naive T cells and B cells produced in the thymus and bone marrow every day, only about 3 to 5 percent of T cells and 10 to 20 percent of B cells pass positive and negative selection steps to reach the periphery and enter the "race" that was described.

As for proteins, more than two-thirds of the IgA (an acquired immune system protein useful in protecting mucosal surfaces—eyes, mouth, etc.) produced by the body every day (more than three grams per day for a 155-pound person) is secreted onto the body's mucosal surfaces for short-term disposal. Immunoglobulins also account for a significant fraction of total blood protein (second only to albumin) and must be replenished continually at a rate of about six grams of immunoglobulins per day for a 155-pound person. Clearly, maintaining the immune system is a demanding process for the human body.

On the cellular level, upon activation, a lymphocyte doubles the amount of intracellular energy (ATP—that is, adenosine triphosphate) committed to protein synthesis (up to 20 percent of total cell energy use), while nucleotide synthesis begins consuming about 10 percent of the cell's energy. This ATP is ultimately derived from dietary macronutrients (protein, carbohydrate, or fat) through metabolic steps that require thiamin, riboflavin, biotin, pantothenic acid, and niacin. When ATP supply is limited, protein and nucleotide syntheses are the first cellular processes to suffer. The building of proteins and nucleotides from amino acids also requires folate, vitamin B6, and vitamin B12 as the essential cofactors. Enzymes that build immunologically active proteins and cells also rely on diet-derived transitional metal atoms (iron, zinc, copper, etc.) for stability and to serve as functional centers. For example, ribonucleotide reductase is a rate-limiting enzyme in nucleotide synthesis, but the only way to maintain the loosely bound iron atom in its functional center is with adequate dietary iron intake. When deprived of multiple nutrients during malnutrition, these immunological processes are clearly compromised as exemplified by reduced thymus mass, lower IgA secretion, and poor proliferation of immune cells in vitro.

Signaling and Gene Regulation

The ability to expand or direct an immune response depends on communication between and within cells. In the innate immune system, various cells can produce signaling molecules (eicosanoids, chemokines, etc.) that attract phagocytes to the site of a challenge (inflammation) while alerting the rest of the immune system. In the acquired immune system, the adaptation of immune cells can be directed toward more efficacious products by signals between cells (cytokines, receptor interaction, etc.) and inside of cells (intracellular signaling molecules, nuclear binding factors, etc.).

Perhaps the clearest relationship between essential nutrients and immune system signaling is the transformation of dietary essential fatty acids into eicosanoids. Certain kinds of fat, which synthesize polyunsaturated fatty acids, are essential to life. These fatty acids are classified as omega-3 or omega-6 fatty acids based on their chemical structure. These fatty acids are used by the body to manufacture eicosanoids (prostaglandins, thromboxanes, and leukotrienes) that regulate inflammation and other body functions. At a molecular level, the distinction between dietary intake of omega-3 versus omega-6 fats is functionally important since eicosanoids derived from omega-3 fats do not produce as much inflammation as omega-6 fats.

An area of immunological research that has rapidly expanded in recent years is the discovery and characterization of proteins that carry signals between the cell surface and nucleus as well as where these proteins bind within various genes. Both vitamin A and vitamin D regulate gene expression by binding to specific gene sequences including, for example, the genes that regulate production of the antiviral protein interferon-gamma. A deficiency of either of these vitamins can impair immune function. Pharmacological doses of vitamin D have been
investigated for their therapeutic potential in autoimmune disorders.

Immune system cells also initiate intracellular signals in response to oxidation. Oxidative stress induces expression of intracellular proteins (AP-1 and NF-kB), which leads to increased production of pro-inflammatory signaling molecules (such as cytokines and chemokines) and their receptors. Vitamin E, vitamin C, and other antioxidants can reduce NF-kB expression, which may contribute to their wide variety of effects on the immune system. Intracellular oxidation state also may alter acquired immune responses, but further research is needed to determine if dietary antioxidants can modify oxidation-sensitive genes and proteins.

Life-Cycle Stages

Different stages of the life cycle have unique nutritional demands and are characterized by unique immunological functionality. Both young children and the elderly have clear age-related immune function deficiencies. In addition, many children in the United States do not meet their daily requirements for several immunologically relevant nutrients, including vitamin E, iron, zinc, and vitamin B6. The elderly may also have difficulty meeting their requirements for vitamin B12, zinc, vitamin E, iron, vitamin D, and vitamin B6 as a result of physiological changes due to aging or to inadequate dietary intakes. Pregnant and lactating women are remarkable because they produce acquired immune system products for the sole apparent purpose of export to the infant. Likewise, pregnant and lactating women frequently do not meet their nutritional demands for folate, vitamin B6, iron, and zinc. Few studies have examined the interaction between nutrients and life-cycle–dependent immune outcomes in otherwise healthy people, but the available data indicate that these interactions have immunological impact—for example, vitamin E among the elderly and iron among postpartum women. Given the susceptibility of these populations to infectious disease, a better understanding of nutrient-immune life-cycle interactions is needed to promote optimal immune status through adequate nutrition.

Nonnutritive Food Components and the Immune Response

For immunologists, developing more efficacious vaccines and certain anticancer agents is a process of improving immune system performance. As nutritional paradigms have shifted from preventing deficiency to promoting optimal health, nutrition scientists have also sought to improve immune system performance. Many in vivo studies have examined more or less purified food components like phytochemicals (polyphenols), herbs, and carotenoids. Such studies frequently use classic immunological tests—cell proliferation, blood lymphocyte counts, skin hypersensitivity responses, etc.—but the results of these tests should be interpreted with caution. For example, a food component that increases cell proliferation may be beneficial if it is the protective cells that proliferate more readily. Conversely, increased cell proliferation would be harmful if autoreactive T-cell or B-cell clones were expanded or inflammatory responses were boosted inappropriately. Although these measures are useful for preliminary identification of nutrient-immune interactions, additional studies using efficacy-related immune measures (infectious disease risk, vaccine titers, etc.) are needed before such phenomena can be termed beneficial.

Summary

To maintain immunological competence, the immune system must quickly alert the body to foreign challenges and rapidly manufacture the cells and proteins needed to stop exponentially dividing infectious organisms. It is apparent that some essential nutrients are signaling molecules. Others can be rate-limiting factors in cell division and protein synthesis. The brevity of this review has prohibited the exploration of many other important nutritional immunology topics: nutrient interactions with infectious agents, treatment of autoimmune disorders, cancer biology, and metabolic functions of nutrients unrelated to biosynthesis or signal transduction. Clearly, the most venerable nutritional paradigms of growth and development are important for shaping the magnitude and character of immune responses.

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Immune System Development

Immune system development

Definition

The child's immune system is an intricate network of interdependent cell types, substances, and organs that collectively protect the body from bacterial, parasitic, fungal, viral infections, and tumor cells.

Description

The immune system was not recognized as a functional unit of the body until the late twentieth century,
probably because its parts are not directly connected to each other and are spread in different parts of the body.

Organs of the immune system

The immune system contains the following organs and cells: tonsils and adenoids; the thymus gland; lymph nodes; bone marrow; and white blood cells that leave blood vessels and migrate through tissues and lymphatic circulation. The spleen, appendix, and patches of lymphoid tissue in the intestinal tract are also parts of the immune system.

The essential job of this system is to distinguish self-cells from foreign substances and to recognize and take protective action against any materials that ought not to be in the body, including abnormal and damaged cells. The immune system can seek out and destroy disease germs, infected cells, and tumor cells. The immune system includes the following cells:

T lymphocytes (T cells)

B lymphocytes (B cells)

natural killer cells (NK cells)

dendritic cells

phagocytic cells

complement proteins

These cells develop from "pluripotential hematopoietic stem cells" starting from a gestational age of about five weeks. They circulate through various organs in the lymphatic system as the fetus develops. T and B lymphocytes are the only units of the immune system that have antigen-specific recognition powers; they are responsible for adaptive immunity. In other words, the T and B cells are important in the immunity that vaccination promotes.

How immunity works

The lymphatic system is a key participant in the body's immune actions. It is a network of vessels and nodes unified by the circulatory system. Lymph nodes occur along the course of the lymphatic vessels and filter lymph fluid before it returns to the bloodstream. The system removes tissue fluids from intercellular spaces and protects the body from bacterial invasions.

Types of immunity

Immunity is the ability of the body to resist the infecting agent. When an infectious agent enters the body, the immune system develops antibodies which can weaken or destroy the disease-producing agent or neutralize its toxins. If the body is re-introduced to the same agent at a later time, it is capable of developing antibodies at a much faster pace. As a result, the individual would likely not become sick, and immunity has developed.

Natural immunity is present when a person is immune to a disease despite not having either the disease itself nor any vaccination against it. Acquired immunity may be either active or passive. Active immunity comes from having the disease or by inoculation with antigens, such as dead organisms, weakened organisms, or toxins of organisms. The antigens introduced during vaccination produce antibodies that protect the body against the infecting agent, despite the fact that the person does not become sick. Passive immunity is relatively short lived and is acquired by transferring antibodies from mother to child in the uterus or by inoculation with serum that contains antibodies from immune persons or animals. Passive immunization is used to help a person who has been exposed or is already infected to fight off disease. Although various types of serums may be used to produce passive immunization, gamma globulin is the most frequently used source of human antibodies.

Development of the immune response

Normal infants have the capability to develop responses to antigens at birth. Infants also start life with some immunoglobulin antibodies acquired from the mother. These antibodies cross the placental barrier, but not all types are transmitted equally. In particular, infants start with antibodies to viruses and gram-positive organisms, but not to gram-negative organisms. Gram is the name of a stain that distinguishes broad classes of bacteria. Gram-negative organisms are responsible for many diseases, including gonorrhea, pertussis (whooping cough), salmonella poisoning, and cholera. Escherichia coli (E. coli) is another common gram-negative organism.

Immunoglobulin antibodies are divided into five classes. The capacity of the body to produce each immunoglobulin varies with age. Newborn babies (premature and full-term) begin to synthesize antibodies at an increased rate soon after birth in response to antigenic stimulation of their new environment. At about six days after birth the serum concentration of specific antibodies rises sharply, and this rise continues until adult levels are achieved by approximately the end of the first year. Maternal immunity gradually disappears during the first six to eight months of life. A concentrated level of antibodies is reached and maintained by seven to eight years of age.

Common problems

Persistent infections

One of the greatest strains on the immune system is an infection it cannot remove. Parents should pay attention to unexplained fevers; night sweats; or tender, swollen lymph nodes. These symptoms can signify a hidden infection or cancer . Infections of the mouth and gums as well as sexually transferred infections often go unnoticed while they drain the vitality of the immune system.

Indiscriminate use of antibiotics

When the immune system successfully controls an infection on its own, it becomes stronger and better able to handle future threats. Antibiotics are powerful medicines that should be given only when the immune system cannot contain a bacterial infection. Overuse of antibiotics may cause the body to breed new strains of antibiotic-resistant or more dangerous bacteria. In the long run, overuse of antibiotics weakens the immune system.

Misuse of immunosuppressive drugs

Immunosuppressive drugs used in cancer chemotherapy or to suppress rejection of organ transplants are necessary. Of greater concern is the widespread use of corticosteroids or steroid derivatives used to treat allergies , autoimmune diseases, and inflammatory conditions. Though sometimes necessary, these drugs cripple the immune response and are often misunderstood, abused, and over-prescribed.

Radiation and hazardous chemicals

Exposure to radiation and hazardous chemicals may also damage the immune system. Excessive radiation of diagnostic x rays of the neck and chest may damage the thymus gland behind the breastbone. The thymus gland is an integral part of the immune system.

Blood transfusions and injections of blood products

Blood transfusions and injections of blood products may broadcast viral diseases like hepatitis that stress the immune system by flooding it with foreign proteins. In an emergency it may not be possible to do without blood transfusions. Sources of blood and blood products are regulated and screened for infectious substances and were as of 2004 much safer.

Other factors

Certain factors have damaging effects on the immune system of infants. Excessive consumption of alcohol during pregnancy leads to depressive levels of vitamin B and zinc, which are essential to immune competence. Alcoholism can also reduce the uptake of several other important nutrients needed for neonatal immune systems. Prolonged stress during pregnant and in breastfeeding mothers reduces the effectiveness of the immune system as well as the quality of immunologic factors in breast milk.

Toxic points—areas of localized infections such as dental abscesses or infected tonsils—may disturb the normal neutralization and weaken the cellular defenses in pregnant mothers and in children.

Deficiencies of many nutrients, especially certain vitamins and minerals , may weaken the immune system. Excessive exercise may depress the immune system temporarily.

Autoimmunity

Autoimmunity occurs when the immune system mistakenly attacks the body's own tissues, resulting in disease that can be mild or severe. Common autoimmune disorders are rheumatoid arthritis, glomerulonephritis, rheumatic fever , and systemic lupus erythematosus (SLE). Autoimmune reactions may be set off by infection, tissue injury, or emotional trauma in people with a genetic tendency to them.

Parental concerns

Parents may be concerned that children with acute illnesses have compromised immune systems and are less likely to have a positive response to vaccines or may be more likely to develop adverse reaction to the vaccine than healthy children. Parents may also believe that children who are ill should not further burden an immune system already committed to fighting an infection.

Most pediatricians would agree that there should be a delay in vaccinations for children with severe illnesses until the symptoms of illness are gone. The reason for deferring immunization is to avoid superimposing a reaction to the vaccine on the underlying illness or attributing symptoms of the underlying illness to the vaccine by mistake. However, a low-grade fever or cold is not a contraindication for routine vaccinations.

Parents may also be concerned that the many different vaccines that infants are given may overwhelm a child's immune system. However, infants have the capacity to respond to large numbers of antigens. Parents who worry about the increasing number of recommended vaccines may take comfort in knowing that children are exposed to fewer antigens in vaccines as of the early 2000s than in previous decades. Two reasons account for this decline: the worldwide elimination of smallpox and advances in protein chemistry in vaccines with fewer antigens.

Vaccines may cause temporary suppression of delayed-type hypersensitivity skin reactions or alter certain lymphocyte function tests. However, the short-lived immunosuppression caused by certain vaccines does not result in an increased risk of infections from other pathogens soon after vaccination.

KEY TERMS

Antibody—A special protein made by the body's immune system as a defense against foreign material (bacteria, viruses, etc.) that enters the body. It is uniquely designed to attack and neutralize the specific antigen that triggered the immune response.

Antigen—A substance (usually a protein) identified as foreign by the body's immune system, triggering the release of antibodies as part of the body's immune response.

Corticosteroids—A group of hormones produced naturally by the adrenal gland or manufactured synthetically. They are often used to treat inflammation. Examples include cortisone and prednisone.

Immune system—The system of specialized organs, lymph nodes, and blood cells throughout the body that work together to defend the body against foreign invaders (bacteria, viruses, fungi, etc.).

Immunization—A process or procedure that protects the body against an infectious disease by stimulating the production of antibodies. A vaccination is a type of immunization.

Lymphocyte—A type of white blood cell that participates in the immune response. The two main groups are the B cells that have antibody molecules on their surface and T cells that destroy antigens.

Phagocytosis—A process by which certain cells envelope and digest debris and microorganisms to remove them from the blood.

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Immune System

UXL Encyclopedia of Science
COPYRIGHT 2002 The Gale Group, Inc.

Immune system

The immune system in a vertebrate (an organism with a backbone) consists of all the cells and tissues that recognize and defend the body against foreign chemicals and organisms. For example, suppose that you receive a cut in your skin. Microorganisms living on your skin are then able to enter your body. They pass into the bloodstream and pass throughout your body. Some of these microorganisms are pathogenic, that is, they may cause illness and even death. As soon as those microorganisms enter your body, its immune system begins to identify them as foreign to your body and to produce defenses that will protect your body against any diseases they may cause.

The study of the immune system is known as immunology and scientists engaged in this field of research are immunologists. Our understanding of the way in which the immune system functions in animals has made possible the prevention of various diseases by means of immunizations. The term immunization refers to the protection of an individual animal against a disease by the introduction of killed or weakened disease-causing organisms into its bloodstream.

Proteins: Large molecules that are essential to the structure and functioning of all living cells.

Specific defenses: Immune responses that target specific antigens.

Vaccination: Introducing antigens into the body in order to make memory cells, thereby reducing the likelihood of contracting future diseases caused by those antigens.

Levels of defense

The immune system consists of three levels of response: external barriers; nonspecific responses; and specific responses. Included among the external barriers are the skin and mucous membranes. An animal's skin acts something like a protective wrapping that keeps diseasecausing organisms out of the body. Normally, the skin is covered with

Interferons

One of the most exciting new disease-fighting agents is a class of compounds known as interferons. Interferons were first discovered in 1957 by Alick Isaacs and Jean Lindenmann. Isaacs and Lindenmann found that chick embryos injected with the influenza virus released very small amounts of a protein that destroyed the virus. The protein also prevented the growth of any other viruses in the embryos. Isaacs and Lindenmann suggested the name interferon for the protein because of its ability to interfere with viral growth.

Further research showed that interferon was produced within hours of a viral invasion and that most living things (including plants) make the protective protein. Scientists realized that interferons were the first line of defense against viral infection in a cell. They realized that interferons might be effective in treating a number of viral diseases in humans, such as some forms of cancer, genital warts, and multiple sclerosis.

Interferons are classified into two general categories, Type I and Type II. Type I interferons are made by every cell in the body, while Type II interferons are made only by T cells and natural killer (NK) cells. Interferons are also classified according to their molecular structure as alpha, beta, gamma, omega, and tau interferons.

In 1986, interferon-alpha became the first interferon to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of disease, in this case, for hairy-cell leukemia. In 1988, this class of interferons was also approved for the treatment of genital warts, proving effective in nearly 70 percent of patients who do not respond to standard therapies. In that same year, it was approved for treatment of Kaposi's sarcoma, a form of cancer that appears frequently in patients suffering from AIDS.

In 1993, another class of interferon, interferon-gamma, received FDA approval for the treatment of one form of multiple sclerosis characterized by the intermittent appearance and disappearance of symptoms. Interferon-gamma may also have therapeutic value in the treatment of leishmaniasis, a parasitic infection that is prevalent in parts of Africa, North and South America, Europe, and Asia.

untold numbers of organisms, some that are harmless, but others that can cause disease. Virtually none of these organisms has the ability to penetrate the skin. Only when the skin has been broken, as in a cut, can the organisms pass into the body.

Mucous membranes are tissues that excrete a thick, sticky liquid known as mucus. All openings that lead to the interior of the body—the mouth, nose, anal tract, and digestive tract—are covered with mucous membranes. Organisms that try to enter the body through one of these openings tend to become trapped in the mucus, preventing them from entering the body.

Nonspecific immune system. Organisms that manage to penetrate the body's first line of defense then encounter another hurdle: the body's nonspecific immune system. The term nonspecific means that this line of defense goes into operation whenever any kind of foreign material enters the body. The immune systems of animals have developed the ability to tell the difference between its own cells, that is, cells produced by the body, and any other kind of material. The foreign matter might be another kind of organism, such as a bacterium or virus; cells from another animal; or inanimate matter, such as coal dust, pollen, cigarette smoke, or asbestosis fibers. Anything that causes an immune response in an animal is said to be an antigen.

Identification of foreign particles as "not-me" cells is made by a group of white blood cells known lymphocytes. Lymphocytes search out antigens in the bloodstream and destroy them by phagocytosis. Phagocytosis is the process by which one cell surrounds a second cell and engulfs it. Once the foreign cell has been swallowed up by the lymphocyte, it is digested by enzymes released from the lymphocyte.

The invasion of antigens can also produce an inflammatory response. Suppose you cut your finger on a tin can. The cut soon becomes red, swollen, and warm. These signs are evidence of the inflammatory response. Injured tissues send out signals to immune system cells, which quickly migrate to the injured area. These immune cells perform different functions. Some destroy bacteria by phagocytosis. Others release enzymes that kill the bacteria. Still other cells release a substance called histamine. Histamine causes blood vessels to dilate (become wider), thus increasing blood flow to the area. All of these activities promote healing in the injured tissue.

Allergic reactions are examples of an inappropriate inflammatory response. When a person is allergic to pollen, the body's immune system is reacting to pollen (a harmless substance) as if it were a bacterium and an immune response is

prompted. When pollen is inhaled, it stimulates an inflammatory response in the nasal cavity and sinuses. Histamine is released, which dilates blood vessels and causes large amounts of mucous to be produced, leading to a "runny nose." In addition, histamine stimulates the release of tears and is responsible for the watery eyes and nasal congestion typical of allergies.

To combat these reactions, many people take drugs that deactivate histamine. These drugs, called antihistamines, are available over the counter and by prescription. Some allergic reactions result in the production of large amounts of histamine, which impairs breathing and necessitates prompt emergency care. People prone to these extreme allergic reactions must carry a special syringe with epinephrine (adrenalin), a drug that quickly counteracts this severe respiratory reaction.

Specific immune system. The body's third line of defense against invasion by foreign organisms is the specific immune system. The specific immune system consists of two kinds of lymphocytes known as T lymphocytes and B lymphocytes. The two kinds of cells are sometimes known simply as T cells and B cells. Both kinds of cells are produced in bone marrow. T cells then migrate to the thymus (which gives them the T in their names), where they mature. No one knows where B cells mature.

T cells and B cells differ from nonspecific lymphocytes in that they attack only very specific antigens. For example, the blood and lymph of humans have T cell lymphocytes that specifically target the chicken pox virus, T cell lymphocytes that target the diphtheria virus, and so on. When T cell lymphocytes specific for the chicken pox virus encounters a body cell infected with this virus, the T cell multiplies rapidly and destroys the invading virus.

Two kinds of T cells exist: killer T cells and helper T cells. Killer T cells go directly to the target antigen and attack it. Helper T cells have many different functions, including to help in the development of B cells. Another function is to stimulate the formation of other T cells and the release of various chemicals that aid in the destruction of antigens.

Helper T cells have an especially crucial role in the immune system. Thus, any disease that destroys helper T cells has a devastating effect on the immune system as a whole. HIV (human immunodeficiency virus, which causes AIDS [acquired immunodeficiency syndrome]), for example, infects and kills helper T cells, thus disabling the immune system and leaving the body helpless to stave off infection.

Memory cells. After an invader has been destroyed, some T cells remain behind. These cells are called memory cells. Memory cells give an animal immunity to future attacks by the original invader. Once a person has had chicken pox, memory cells are created. If the person is later exposed to the chicken pox virus again, the virus is quickly destroyed. This secondary immune response, involving memory cells, is much faster than the primary immune response.

The procedure known as vaccination makes use of the above process. Vaccination is the process by which a killed microorganism (or parts thereof) are injected into a person's bloodstream. The presence of these particles prompts the formation of memory cells without a person's having to actually develop the disease.

B cells and the antibody response. When helper T cells recognize the presence of an invading antigen, they stimulate B cells in the blood and lymph to start reproducing. As the B cells reproduce, they also undergo a change in structure and become known as plasma cells. Those plasma cells then begin to secrete compounds known as antibodies. Antibodies are chemicals released by B cells that attach themselves to the surface of an antigen. The presence of an antibody helps other cells in the immune system recognize the antigen and mark it for destruction.

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immune system

immune system Have you ever wondered why you are resistant to the colds that plague your friends, even though you have been exposed to the same environment? This is because you have an efficient immune system which is working overtime to identify and mount a reaction to ‘invaders’, including microorganisms capable of causing disease and foreign macromolecules like polysaccharides and proteins — a phenomenon known as immunity.

Historically, immunity referred to protection from infectious diseases, and the term was derived from the Latin word immunitas, meaning the exemption from civic duties and prosecution extended to Roman senators. However the concept of immunity existed long before, especially in the Chinese custom of making children inhale powders of crust of skin lesions of patients recovering from small pox. The first scientifically documented evidence of inducing immunity was the landmark work of Dr Edward Jenner, an English physician. He noticed that milkmaids who had recovered from cowpox were resistant to contracting small pox. When he injected the material from a cowpox pustule into a young boy, the boy did not develop small pox even when intentionally inoculated. Jenner published his findings in 1798 and laid the foundation for the future development of ‘vaccination’ (the Latin word vacinus means of or from cows) and other forms of immunization.

Two basic levels of immunity exist in healthy individuals to confer protection against microbes and other foreign bodies; the less perfect natural immunity and the more specific acquired immunity.

Natural immunity

Those defence mechanisms that exist prior to exposure to foreign substances, that are not enhanced by subsequent exposures, and that cannot discriminate between most foreign molecules, are categorized as natural or innate immunity. This includes the first line of defence — the protective barriers like the skin and the mucous membranes lining the body tracts, which secrete acids and enzymes capable of digesting bacterial cell walls. Often a failure at this level may lead to fatal complications (such as in cystic fibrosis, where the mucus formed is not protective).

If this protective barrier is breached, the next lines of defence involve two components of natural immunity — the humoral (mediated by substances free in the body fluids) and the cellular (mediated by cells). A number of humoral agents are rapidly produced or activated to exert non-specific effects: that is, they are equally effective against multiple microbes. They include acute phase proteins, serum complements, and interferons. Interferons are vital mainly in controlling viral infections. At this time the cellular component also comes into play. Two types of phagocytic cells ‘eat up’ and destroy the foreign molecules. The first of these are the polymorphonuclear neutrophil leucocytes (white blood cells), which circulate in blood and migrate to sites of microbial invasion; the second are called monocytes in the blood and macrophages in the tissues (they migrate between the two) — collectively, the macrophage–monocyte system. Humoral and cellular mechanisms interact: serum complements bind to the surface of the foreign molecule and increase the efficiency of phagocytosis by the cells.

Acquired immunity

By the time the components of natural immunity perform their act, more specific defence mechanisms are also mounted. These mechanisms are induced by exposure to the foreign molecules which are known as antigens. Besides amplifying the protective mechanisms of innate immunity, the specific immune system also ‘memorizes’ each encounter with a particular antigen such that subsequent exposure to that antigen leads to the development of ‘active immunity’. Specific immunity can also be induced in an individual by transferring cells or serum (depending on the type of immune response, see later) from a specifically immunized individual, so that the recipient becomes immune to the particular antigen without getting an actual exposure to it. This form of immunity is called ‘passive immunity’, and often is a useful method for rapid conferring of immunity. This technique has helped in saving lives following potentially lethal snake bites, by the administration of antibodies from immunized individuals. Much more commonly, anti-tetanus serum has been widely used to confer passive immunity after potentially contaminated minor injuries.

Lymphocytes are the primary players in specific immunity. These are cells that are present throughout the body, circulating in the blood and lymph and organized in lymphoid tissues. They are produced in primary lymphoid organs — the liver in the fetus, the thymus, and the bone marrow. Some lymphocytes pass through the thymus after release from the bone marrow, re-enter the circulation and then settle in secondary lymphoid organs like the spleen and the lymph nodes. During passage through the thymus these lymphocytes acquire antigen specificity, properties which equip them to act against a particular invader, and are thereafter known as T-cells. Other lymphocytes do not pass through the thymus, but settle directly in the secondary lymphoid organs where they mature and develop antigen specificity. These cells are called B-lymphocytes or B-cells; they carry on their surface a ‘recognition molecule’ or antibody, which acts as a receptor for an antigen.

Antibodies belong to a group of proteins called immunoglobulins. They are similar in their overall Y-shaped structure. The 2 arms form the part known as ‘Fab’, which binds with the antigen. Here the amino acid sequence varies widely; these regions determine the specificity of the antibody and also account for the diversity of immunity. In fact there are between 10 and 1000 million structurally different antibodies in an individual, each with unique amino acid sequences in the Fab region. The stem of the antibody determines its biological function, and its properties are used in classifying the immunoglobulins (IgG, IgM, IgA, IgD, and IgE.)

Humoral immunity is mediated by antibodies that are released into the circulation from B-lymphocytes, and can therefore be transferred to non-immunized individuals by cell-free components of blood. It is the principal defence mechanism against extra-cellular foreign molecules or their toxins because the antibodies bind to these and lead to their destruction. Intracellular antigens are handled by cell-mediated immunity, of which the main component is T-lymphocytes. This form of immunity can be transferred only through the cells of the blood. Humoral and cellular immunity are thus the two types of acquired or specific immunity.

Following exposure to an antigen, the specific immune response is brought about in a sequential manner, which can be divided into three phases: ‘cognitive’, ‘activation’ and ‘effector’. During the cognitive phase, the antigen binds to specific receptors on mature lymphocytes of both types. The antibody on B-lymphocytes recognizes and binds foreign proteins, polysaccharides, or lipids in soluble form. Receptors on T-lymphocytes, on the other hand, can recognize only short peptide sequences in protein antigens present on the surface of other cells. In the technical jargon of immunology, the portion of an antigen that is specifically recognized by the antibody is called an ‘epitope’.

Next, in the activation phase, the antigen-specific lymphocytes of both types proliferate by cloning, thus amplifying the immune response. Lymphocytes develop into cells whose primary function is to eliminate the antigen. All clonal B-cells secrete the same antibody, which combines with the antigen and initiates a sequence of events leading to destruction of that antigen. Subsets of the antigen-specific T-cell clones develop different functions; some activate phagocytes; others, called T-cytotoxic cells, directly break down cells that produce viral antigens; some regulate the production of antibody by B-cells. Those T-cells, which promote the immune response, are called T-helper cells, while others that inhibit it as part of the self-limiting capability of the immune response, are called T-suppressor cells. Another subset, the Tdth cells (delayed type hypersensitivity) produce factors that modulate the functions of lymphocytes and macrophages.

A set of membrane proteins that are products of genes determining (in)compatibility of tissues between individuals are known as HLA (called human lymphocyte antigens, because they were first recognized on these cells, but they occur on other cells also). They regulate the T-cell activity in such a way that T-cells recognize other antigens only when they are associated with the HLA molecules. This system is highly variable in the human population and it is rare for two individuals to have the same HLA products. This is often the reason for transplant rejection due to an immune response, when the donor's proteins serve as antigens in the recipient. HLA typing and matching is thus an essential step before any transplant surgery to minimize the chances of an immune response.

Once the lymphocytes have been activated and the antigen has been presented to them, the immune response enters the effector phase. Few antigens bind directly to antigen-reactive T- or B-cells but are presented to the lymphocytes bound to other ‘antigen presenting cells’ such as macrophages. The effector phase requires the participation also of other non-lymphoid ‘effector cells’ such as mast cells, eosinophils, or natural killer (NK) cells, which act also as components of natural immunity. Antibodies bind to the antigen, and this promotes phagocytosis by neutrophils or other phagocytes. Antibodies can also activate the ‘complement system’, generating proteins that cause inflammation, cell breakdown, and phagocytosis of the antigen. Some antibodies, like IgA released from mucous membranes, coat the antigen and prevent its docking on the epithelial lining of body tracts. T-cells also secrete chemicals called cytokines, which stimulate an inflammatory response and enhance the function of natural immunity. The antigen thus faces a barrage of defence mechanisms' which leads to its destruction.

Once the antigenic stimulation is removed, lymphocytes become quiescent and only some remain viable as memory cells. On a subsequent exposure to the same antigen these become rapidly activated and can mount a faster response than the first time, called the secondary immune response. A series of feedback controls also come into play, which makes the immune response self limiting.

One of the distinguishing and essential features of the immune system is its ability to discriminate between foreign and ‘self-antigens’. Immunity is unresponsive to molecules present in the individual that would be antigenic in another. This arises due to an acquired process called self-tolerance. Thus during the early stages of development, functionally immature ‘self-recognizing’ lymphocytes come in contact with self-antigens and are prevented from developing to a stage where they can respond to self-antigens. However, in certain unfortunate conditions, abnormalities in induction or maintenance of self-tolerance may occur, which leads to the immune system acting against a normal component of the same body. This leads to the development of autoimmune diseases.

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Immune System

World of Microbiology and Immunology
COPYRIGHT 2003 The Gale Group Inc.

Immune system

The immune system is the body's biological defense mechanism that protects against foreign invaders. Only in the last century have the components of that system and the ways in which they work been discovered, and more remains to be clarified.

The true roots of the study of the immune system date from 1796 when an English physician, Edward Jenner , discovered a method of smallpox vaccination . He noted that dairy workers who contracted cowpox from milking infected cows were thereafter resistant to smallpox. In 1796, Jenner injected a young boy with material from a milkmaid who had an active case of cowpox. After the boy recovered from his own resulting cowpox, Jenner inoculated him with smallpox; the boy was immune. After Jenner published the results of this and other cases in 1798, the practice of Jennerian vaccination spread rapidly.

It was Louis Pasteur who established the cause of infectious diseases and the medical basis for immunization . First, Pasteur formulated his germ theory of disease , the concept that disease is caused by communicable microorganisms . In 1880, Pasteur discovered that aged cultures of fowl cholera bacteria lost their power to induce disease in chickens but still conferred immunity to the disease when injected. He went on to use attenuated (weakened) cultures of anthrax and rabies to vaccinate against those diseases. The American scientists Theobald Smith (1859–1934) and Daniel Salmon (1850–1914) showed in 1886 that bacteria killed by heat could also confer immunity.

Why vaccination imparted immunity was not yet known. In 1888, Pierre-Paul-Emile Roux (1853–1933) and Alexandre Yersin (1863–1943) showed that diphtheria bacillus produced a toxin that the body responded to by producing an antitoxin. Emil von Behring and Shibasaburo Kitasato found a similar toxin-antitoxin reaction in tetanus in 1890. Von Behring discovered that small doses of tetanus or diphtheria toxin produced immunity, and that this immunity could be transferred from animal to animal via serum. Von Behring concluded that the immunity was conferred by substances in the blood, which he called antitoxins, or antibodies. In 1894, Richard Pfeiffer (1858–1945) found that antibodies killed cholera bacteria (bacterioloysis). Hans Buchner (1850–1902) in 1893 discovered another important blood substance called complement (Buchner's term was alexin), and Jules Bordet in 1898 found that it enabled the antibodies to combine with antigens (foreign substances) and destroy or eliminate them. It became clear that each antibody acted only against a specific antigen . Karl Landsteiner was able to use this specific antigen-antibody reaction to distinguish the different blood groups.

A new element was introduced into the growing body of immune system knowledge during the 1880s by the Russian microbiologist Elie Metchnikoff. He discovered cell-based immunity: white blood cells (leucocytes), which Metchnikoff called phagocytes, ingested and destroyed foreign particles. Considerable controversy flourished between the proponents of cell-based and blood-based immunity until 1903, when Almroth Edward Wright brought them together by showing that certain blood substances were necessary for phagocytes to function as bacteria destroyers. A unifying theory of immunity was posited by Paul Ehrlich in the 1890s; his "side-chain" theory explained that antigens and antibodies combine chemically in fixed ways, like a key fits into a lock. Until this time, immune responses were seen as purely beneficial. In 1902, however, Charles Richet and Paul Portier demonstrated extreme immune reactions in test animals that had become sensitive to antigens by previous exposure. This phenomenon of hypersensitivity, called anaphylaxis , showed that immune responses could cause the body to damage itself. Hypersensitivity to antigens also explained allergies , a term coined by Pirquet in 1906.

Much more was learned about antibodies in the mid-twentieth century, including the fact that they are proteins of the gamma globulin portion of plasma and are produced by plasma cells; their molecular structure was also worked out. An important advance in immunochemistry came in 1935 when Michael Heidelberger and Edward Kendall (1886–1972) developed a method to detect and measure amounts of different
antigens and antibodies in serum. Immunobiology also advanced. Frank Macfarlane Burnet suggested that animals did not produce antibodies to substances they had encountered very early in life; Peter Medawar proved this idea in 1953 through experiments on mouse embryos.

In 1957, Burnet put forth his clonal selection theory to explain the biology of immune responses. On meeting an antigen, an immunologically responsive cell (shown by C. S. Gowans (1923– ) in the 1960s to be a lymphocyte) responds by multiplying and producing an identical set of plasma cells, which in turn manufacture the specific antibody for that antigen. Further cellular research has shown that there are two types of lymphocytes (nondescript lymph cells): B-lymphocytes, which secrete antibody, and T-lymphocytes , which regulate the B-lymphocytes and also either kill foreign substances directly (killer T cells ) or stimulate macrophages to do so (helper T cells). Lymphocytes recognize antigens by characteristics on the surface of the antigen-carrying molecules. Researchers in the 1980s uncovered many more intricate biological and chemical details of the immune system components and the ways in which they interact.

Knowledge about the immune system's role in rejection of transplanted tissue became extremely important as organ transplantation became surgically feasible. Peter Medawar's work in the 1940s showed that such rejection was an immune reaction to antigens on the foreign tissue. Donald Calne (1936– ) showed in 1960 that immunosuppressive drugs, drugs that suppress immune responses, reduced transplant rejection, and these drugs were first used on human patients in 1962. In the 1940s, George Snell (1903–1996) discovered in mice a group of tissue-compatibility genes, the MHC , that played an important role in controlling acceptance or resistance to tissue grafts. Jean Dausset found human MHC, a set of antigens to human leucocytes (white blood cells), called HLA . Matching of HLA in donor and recipient tissue is an important technique to predict compatibility in transplants. Baruj Benacerraf in 1969 showed that an animal's ability to respond to an antigen was controlled by genes in the MHC complex.

Exciting new discoveries in the study of the immune system are on the horizon. Researchers are investigating the relation of HLA to disease; certain types of HLA molecules may predispose people to particular diseases. This promises to lead to more effective treatments and, in the long run, possible prevention. Autoimmune reaction, in which the body has an immune response to its own substances, may also be a cause of a number of diseases, like multiple sclerosis, and research proceeds on that front. Approaches to cancer treatment also involve the immune system. Some researchers, including Burnet, speculate that a failure of the immune system may be implicated in cancer. In the late 1960s, Ion Gresser (1928– ) discovered that the protein interferon acts against cancerous tumors. After the development of genetically engineered interferon in the mid-1980s finally made the substance available in practical amounts, research into its use against cancer accelerated. The invention of monoclonal antibodies in the mid-1970s was a major breakthrough. Increasingly sophisticated knowledge about the workings of the immune system holds out the hope of finding an effective method to combat one of the most serious immune system disorders, AIDS .

Avenues of research to treat AIDS includes a focus on supporting and strengthening the immune system. (However, much research has to be done in this area to determine whether strengthening the immune system is beneficial or whether it may cause an increase in the number of infected cells.) One area of interest is cytokines , proteins produced by the body that help the immune system cells communicate with each other and activate them to fight infection. Some individuals infected with the AIDS virus HIV (human immunodeficiency virus ) have higher levels of certain cytokines and lower levels of others. A possible approach to controlling infection would be to boost deficient levels of cytokines while depressing levels of cytokines that may be too abundant. Other research has found that HIV may also turn the immune system against itself by producing antibodies against its own cells.

Advances in immunological research indicate that the immune system may be made of more than 100 million highly specialized cells designed to combat specific antigens. While the task of identifying these cells and their functions may be daunting, headway is being made. By identifying these specific cells, researchers may be able to further advance another promising area of immunologic research, the use of recombinant DNA technology, in which specific proteins can be mass-produced. This approach has led to new cancer treatments that can stimulate the immune system by using synthetic versions of proteins released by interferons .

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Immune System Genetics

Genetics
Copyright Genetics Society of America

Immune System Genetics

The immune system is the set of cells and glands that protects the body from invasion and infection by viruses, bacteria, and other pathogens . The immune system must be able to recognize any foreign target, or antigen, of which there are potentially millions. Pathogenic organisms change over time, and new antigens evolve that must also be targeted. At the same time, the immune system must distinguish pathogenic antigens from the body's own tissues, attacking the former and sparing the latter. The key to the scope and specificity of the immune system response is in the genes that give rise to it.

Overview of the Immune System

The immune system includes several interacting components. Nonspecific immunity (protection against any invasion) is provided by the barriers of the skin and mucous membranes lining the lungs and gut. Additional non-specific defenses are provided by the inflammatory response and the complement proteins in the bloodstream. We shall not deal further with these defenses.

Specific immunity is the set of defenses mounted against a specific invader. It involves the action of three major types of cells: B cells, T cells, and macrophages. In broad, somewhat oversimplified terms, B cells make proteins called antibodies that attach to foreign antigens, serving as warning flags. T cells coordinate the immune attack and destroy virus-infected cells. Macrophages consume flagged antigens and clean up the debris from a T cell attack on infected cells.

An antibody binds to an invader when its shape fits some shape (the antigen) on the invader's surface. Any particular invader, such as a bacterial cell, may have dozens of such antigens.

The Puzzle of Antibody Diversity

B cells are created in the bone marrow. Many millions of different B cells are made, each containing a unique gene for the specific antibody that it (and all its descendants) will make. A group of B cells with all its descendants
is called a clone. Thus, the antibody made by one B cell clone differs from that made by any other B cell clone. T cells develop along a slightly different pathway but also contain a unique protein, called the T cell receptor, which is coded for by a gene unique to that T cell clone.

Antibodies are proteins, and like all of the body's proteins, must be encoded by genes. However, the number of distinct antibodies each of us makes (many millions) is vastly greater than the total number of genes in our entire genome (30,000-70,000). How is all this diversity encoded? To understand the answer, it is helpful to look at the structure of an antibody.

Antibody Structure

The antibody is formed from four polypeptides that link up in the shape of a Y. There are two identical long heavy (H) chains and two identical short light (L) chains. The tips of each branch of the Y form a pocket, and it is here the antibody binds antigen. Thus, these twin pockets are called the antigen-binding regions of the antibody.

By comparing the amino acid sequences of antibodies from different B cell clones, several important features can be discovered. Light chains, for instance, have a constant region, with amino acid sequences that differ little from clone to clone, and a variable region, with sequences that differ considerably. The constant region comes in two different forms, termed "kappa" and "lambda." The amino acid sequence of one kappa constant sequence differs little or not at all from clone to clone; similarly, all lambda constant sequences are essentially identical. The variable region does differ considerably between clones. The heavy chain also has a constant region (of which there are five forms) and a variable region.

The constant regions of all the chains are found toward the bottom of the Y, while the variable regions are found toward the tip. Furthermore, within each variable region, there are three hypervariable regions, whose five to ten amino acids differ even more than the other portions of the variable region. These hypervariable regions form the actual points of contact between antibody and antigen.

Gene Segments Combine Randomly to Generate Diversity

The fundamental principle governing antibody generation is combinatorial diversity. A large number of genes are generated by choosing from among a smaller pool of differing gene segments and combining them in different ways. This process, known as somatic recombination, is similar in principle to constructing words. The alphabet's twenty-six letters can be combined to make 676 (262) two-letter words and almost 12 million five-letter words.

To understand the molecular details of somatic recombination, let us focus on the creation of a kappa-type light chain. The process is similar for lambda light chains and only marginally more involved for a heavy chain.

We noted that the light chain has both a variable and a constant region. There are forty gene segments that can code for the variable (V) region and a single segment that codes for the constant (C) region. In addition, there are five possible coding segments for the J region, a short region that is also present on light chains. All of these genes and segments are located in sequence on chromosome 2. Each V and J segment is flanked by special noncoding sequences that facilitate the next stage, in which specific segments are joined.

Somatic recombination begins when special recombining proteins randomly bring together the downstream end of one V segment and the upstream end of one J segment. They do this by attaching to the flanking sequences and bending the intervening DNA into a loop. The loop is cut out and degraded, and the remaining DNA is spliced together. The product is the mature antibody gene.

Note in the diagram on the right that the resulting gene may still have some extra upstream V segments. An ingenious mechanism prevents such segments from being transcribed to make messenger RNA, however.

Each V segment contains a promoter , the region to which RNA polymerase binds to start transcription. The promoter is inactive, though, until it is brought close to an "enhancer" region between the J and C segments. Thus, transcription will begin at the V segment closest to the enhancer, and only this one V segment is transcribed—the others are too far from the enhancer. The gene may also have extra downstream J segments and intron sequences between J and C. These are transcribed, but they are removed by RNA processing.

Other Sources of Diversity

The random combination of V and J segments alone can produce millions of possible combinations. More diversity arises because the joining of V and J chains is done imprecisely, with the possible loss or gain of several nucleotides, resulting in added or deleted amino acids.

Remember also that each antibody includes both light and heavy chains. Heavy chains are produced by a similar combinatorial process, using a different, larger set of gene segments. The combination of a randomly produced light chain with a randomly produced heavy chain produces even more diversity. Finally, when a B cell multiplies in response to antigens, the
rearranged gene can mutate, making some members of the clone different from others. The number of possible antibodies available through all these processes is in the trillions.

T Cell Receptors

As mentioned above, T cells help control the immune response and kill infected cells. Infected cells are recognized because they chop up foreign proteins from the invader and display the bits on their surface. These bits, which are antigens, are held aloft by surface proteins, called MHC (major histocompatibility complex) proteins. The MHC-antigen complex is recognized by the T cell receptor, in cooperation with one or more other T cell surface molecules.

When a T cell discovers a cell whose MHC proteins contain foreign antigens, it marks the cell for destruction. The T cell receptor interacts with antigens in much the same way as an antibody does, although the size of the antigen it recognizes is smaller. T cell receptors come in as many diverse forms as antibodies do, and, while the details differ, their diversity is generated in much the same way, with random recombination of gene segments.

The Major Histocompatibility Complex

The T cell-MHC interaction serves another, related function: It confirms that the cell is part of the self that the immune system should be protecting. Thus, MHCs serve as self-recognition markers. When a T cell recognizes foreign MHCs, as would occur in an organ transplant, it sets in motion an immune attack to reject the foreign tissue. Indeed, "histocompatibility" means compatibility of tissues, and these proteins control that process.

There are two major classes of MHC proteins, called class I and II, with different functions in antigen presentation. Class I contains three members, each coded for by different genes, and class II contains four members. For almost every gene, there are multiple alleles . The number of alleles per gene ranges from a handful to more than 100. Since each person will inherit and express a unique set of MHC alleles, once again we can see the combinatorial possibilities: There are millions of different combinations of MHC alleles, and very few people are likely to have exactly the same set. This is what makes organ transplants so difficult. Matching MHC types is the key to success, but even close relatives may have different allele sets.

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Immune Globulin

Gale Encyclopedia of Cancer
COPYRIGHT 2002 The Gale Group Inc.

Immune globulin

Definition

Immune globulin is a concentrated solution of antibodies, pooled from donated blood, which is sometimes given to cancer patients whose own immune systems are either not working or are suppressed as a side effect of treatment. Immune globulin can also be called gamma globulin; in the United States some of the brand names are Gamimune, Gammagard, Gammar-P, Iveegam, Polygam, Sandoglobulin, and Venoglobulin.

Purpose

A healthy human body produces proteins called antibodies that act to destroy microorganisms (bacteria and viruses) that invade the body. Some cancer patients, due to the illness itself or side effects of treatment, become depleted of these proteins and therefore susceptible to serious infections. Immune globulin is given to these patients to restore their body's immunity. The use of immune globulin in this way is also called passive immunization. For example, immune globulin is given to bone marrow transplant recipients to prevent the development of severe bacterial infections while their own immune system is not functioning, and chronic lymphocytic leukemia patients (of the type whose antibody-producing cells are the malignant cells) are given immune globulin to prevent the recurrent infections these patients sometimes suffer. Use in this disorder also allows the use of aggressive chemotherapy that will destroy the patient's own cancerous antibody-producing cells.

Immune globulin is also used to treat other diseases such as Eaton-Lambert Syndrome , a rare neurological disorder that sometimes occurs in association with small cell lung cancer called Eaton-Lambert syndrome, an autoimmune disease in which a patient's own antibodies attack nerve cells. The use of immune globulin appears to cause the body to reduce its own production of antibody, thereby improving the neurological disorder.

Description

Immune globulin primarily consists of antibody proteins of the type called IgG or gamma, although the solution may contain small amounts of other antibody types as well as sugars, proteins, and salt.

It is produced by pooling donated blood from at least 1000 people who have been tested to be free of blood-borne diseases like HIV or hepatitis. The antibody proteins are then separated out of the whole blood, and the pH of the immune globulin solution is adjusted to match the normal pH of blood. The preparation is also treated to remove any contaminants, including infectious bacteria or viruses.

Recommended dosage

The dose of immune globulin used varies with the specific problem that it is being used for. When immune gobulin is used in patients with Eaton-Lambert Syndrome, the effective dose is usually about 1 g/kg of body weight/day. (One gram equals 0.035274 ounce; one kilogram equals 2.2046 pounds.) When used to counteract immunodeficiency, the dose is designed to produce an antibody level that stays at an effective threshold over a period of time.

When immune globulin is given to bone marrow transplant recipients, it is usually begun at the time of the transplant and continued for 100 days thereafter, with the objective of maintaining the level of IgG in the patient's blood above 400 mg per deciliter. (A deciliter equals 3.38 fluid ounces.) In patients with chronic lymphocytic leukemia (B-cell type) the target threshold for antibodies in the patient's blood is usually about 600 mg/dL. Although the amount required to maintain these levels varies from patient to patient (because different patients metabolize the drug at different rates) a dose between 10 and 200 mg/kg of body weight, given every 3-4 weeks, is usually sufficient.

Immune globulin is usually given intravenously, although intramuscular shots are available.

Precautions

Some people may have experienced severe reactions, including allergy-type reactions, to other antibody preparations. Generally these people should not be given intravenous immune globulin. Patients with deficiency of antibody IgA, specifically, should also avoid the use of immune globulin. People with a tendency to form blood clots, or those with kidney problems should also avoid the use of this product, especially if elderly. While many pregnant women have been treated with immune globulin for different problems that have occurred during their pregnancy, since the method of action and specific effects on the fetus are not completely understood, pregnant women should avoid the use of immune globlulin
unless it is clearly necessary. Any patient who is given immune globulin should be watched carefully, and epinephrine should be kept available in case a severe allergic reaction is experienced. Immune globulin which was made to be given through intramuscular injection should never be administered intravenously.

Side effects

Administration of intramuscular immune globulin may result in tenderness, swelling, and possibly hives at the site of the injection.

Intravenous immune globulin may cause more severe reactions related to rapid introduction into the blood system. Possible side effects include headache, backache, aching muscles, fever , low blood pressure, and chest pain. More commonly, fever accompanied by chills or nausea and vomiting may be experienced. If these side effects occur, they are usually related to the immune globulin being administered too rapidly. If the rate of infusion is reduced, or if the infusion is stopped temporarily, negative effects will generally disappear. Rare, but potentially serious, side effects observed have been kidney failure and aseptic meningitis.

Interactions

Use of immune globulin may reduce the effectiveness of vaccinations (for example, measles, mumps, and rubella) for a few months following the use of the immune globulin preparation. Patients who have been given immune globulin should notify their doctors before any vaccinations are given. In addition, in some situations patients may need to have antibody levels measured to determine whether or not they have had previous infection with a specific microorganism. Use of immune globulin can create the false impression of prior exposure to the organism due to the donated antibodies in their blood.

See Also Immunologic therapies

Wendy Wippel, M.S.

KEY TERMS

Autoimmune disease

—A disease in which the body produces an immunologic reaction against itself.

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Immune System

World of Forensic Science
COPYRIGHT 2005 Thomson Gale

Immune System

A staple in forensic investigations is the use of antibodies to detect a target antigen . Blood typing and the detection of bacteria, or their elaborated toxins , rely on the recognition of antigens by their corresponding antibodies. The production of antibodies is one aspect of the immune system, the body's biological defense mechanism that protects against foreign invaders.

The true roots of the study of the immune system date from 1796, when English physician Edward Jenner discovered a method of smallpox vaccination. He noted that dairy workers who contracted cowpox from milking infected cows were thereafter resistant to smallpox. In 1796, Jenner injected a young boy with material from a milkmaid who had an active case of cowpox. After the boy recovered from his own resulting cowpox, Jenner inoculated him with smallpox; the boy was immune. After Jenner published the results of this and other cases in 1798, the practice of Jennerian vaccination spread rapidly.

Louis Pasteur established the cause of infectious diseases and the medical basis for immunization. Pasteur formulated the germ theory of disease, the concept that disease is caused by communicable microorganisms. In 1880, Pasteur discovered that aged cultures of fowl cholera bacteria lost their power to induce disease in chickens but still conferred immunity to the disease when injected. He went on to use attenuated (weakened) cultures of anthrax and rabies to vaccinate against those diseases. The American scientists Theobald Smith (1859–1934) and Daniel Salmon (1850–1914) showed in 1886 that bacteria killed by heat could also confer immunity.

In 1888, Pierre-Paul-Emile Roux (1853–1933) and Alexandre Yersin (1863–1943) showed that diphtheria bacillus produced a toxin that the body responded to by producing an antitoxin. Emil von Behring and Shibasaburo Kitasato found a similar toxin-antitoxin reaction in tetanus in 1890, and von Behring discovered that small doses of tetanus or diphtheria toxin produced immunity, which could be transferred from animal to animal via serum . He concluded that the immunity was conferred by substances in the blood, which he called antitoxins, or antibodies. In 1894, Richard Pfeiffer (1858–1945) found that antibodies killed cholera bacteria (bacterioloysis). Hans Buchner (1850–1902) in 1893 discovered another important blood substance called complement (Buchner's term was alexin), and Jules Bordet in 1898 found that it enabled the antibodies to combine with antigens (foreign substances) and destroy or eliminate them. It became clear that each antibody acted only against a specific antigen. Karl Landsteiner exploited this specific antigen-antibody reaction to distinguish the different blood groups.

In the 1880s Russian microbiologist Elie Metchnikoff discovered cell-based immunity: white blood cells (leucocytes), which Metchnikoff called phagocytes, ingested and destroyed foreign particles. Considerable controversy flourished between the proponents of cell-based and blood-based immunity until 1903, when Almroth Edward Wright brought them together by showing that certain blood substances were necessary for phagocytes to function as bacteria destroyers. A unifying theory of immunity was posited by Paul Ehrlich in the 1890s; his "side-chain" theory explained that antigens and antibodies combine chemically in fixed ways, like a key fits into a lock. Until now, immune responses were seen as purely beneficial. In 1902, however, Charles Richet and Paul Portier demonstrated extreme immune reactions in test animals that had become sensitive
to antigens by previous exposure. This phenomenon of hypersensitivity, called anaphylaxis, showed that immune responses could cause the body to damage itself. Hypersensitivity to antigens also explained allergies, a term coined by Pirquet in 1906.

Much more was learned about antibodies in the mid-twentieth century, including the fact that they are proteins of the gamma globulin portion of plasma and are produced by plasma cells; their molecular structure was also determined. An important advance in immunochemistry came in 1935 when Michael Heidelberger and Edward Kendall (1886–1972) developed a method to detect and measure amounts of different antigens and antibodies in serum. Immunobiology also advanced. Frank Macfarlane Burnet suggested that animals did not produce antibodies to substances they had encountered very early in life; Peter Medawar proved this idea in 1953 through experiments on mouse embryos.

In 1957, Burnet put forth his clonal selection theory to explain the biology of immune responses. On meeting an antigen, an immunologically responsive cell (shown by C. S. Gowans [1923–] in the 1960s to be a lymphocyte) responds by multiplying and producing an identical set of plasma cells, which in turn manufacture the specific antibody for that antigen. Further cellular research has shown that there are two types of lymphocytes (non-descript lymph cells): B-lymphocytes, which secrete antibody, and T-lymphocytes, which regulate the B-lymphocytes and also either kill foreign substances directly (killer T cells) or stimulate macrophages to do so (helper T cells). Lymphocytes recognize antigens by characteristics on the surface of the antigen-carrying molecules. Researchers in the 1980s uncovered many more intricate biological and chemical details of the immune system components and the ways in which they interact.

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Immune Synapse

World of Microbiology and Immunology
COPYRIGHT 2003 The Gale Group Inc.

Immune synapse

Before they can help other immune cells respond to a foreign protein or pathogenic organism, helper T cells must first become activated. This process occurs when an antigen-presenting cell submits a fragment of a foreign protein, bound to a Class II MHC molecule (virus-derived fragments are bound to Class I MHC molecules) to the helper T cell. Antigen-presenting cells are derived from bone marrow, and include both dendritic cells and Langerhans cells, as well as other specialized cells. Because T cell responses depend upon direct contact
with their target cells, their antigen receptors, unlike antibodies made by B cells , exist bound to the membrane only. In the intercellular gap between the T cell and the antigen-presenting cell, a special pattern of various receptors and complementary ligands forms that is several microns in size. This patterned collection of receptors is called the immune synapse.

The immune synapse can be compared to a molecular machine that controls T cell activation. Physically it consists of a group of T cell receptors surrounded by a ring of integrin-like adhesion molecules as well as other accessory proteins like the CD3 complex. Integrins are a family of cell-surface proteins that are involved in binding to extracellular matrix components. This specialized cell-cell junction was named the immunological synapse because it is thought to be involved in the transfer of information across the T cell-APC junction. Specifically, the immune synapse appears to play an essential role in organizing the immune response, the level of control, and the nature of that response. The formation of the synapse requires several minutes and it appears to be stable for several hours. The structural protein actin seems to have an important role in that stability as T-cell activation is blocked by disruption of actin filaments. There also appears to be a temporal spatial component in that signals that modulate T-cell maturity and functions are received in a serial manner as well as simultaneously. Further clarification of the structure of the immune synapse will help develop further insights into T cell recognition as well as the mechanism of T cell receptor signalinghow information transfer occurs across the synapse. The duration of signaling in immature T cells may control CD4 and CD8 lineage decisions. This would be useful in determining the degree to which different types and developmental stages rely on alternative signaling mechanisms.

See also Antibody and antigen; Antibody formation and kinetics; Antibody-antigen, biochemical and molecular reactions; T cells or T-lymphocytes

Cite this article Pick a style below, and copy the text for your bibliography.

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Immune System

Nutrition and Well-Being A to Z
COPYRIGHT 2004 The Gale Group, Inc.

Immune System

The immune system is made up of cells, tissues, organs, and processes that identify a substance as abnormal or foreign and prevent it from harming the body. Primary defenses include the white blood cells , but skin, mucosa , normal bacteria , enzymes , and proteins also provide protection. During times of stress and malnutrition , immune function may be decreased, meaning that susceptibility to illness is increased. Proper nutrition , including adequate protein, calories , and antioxidants (such as vitamin C, vitamin E, and beta-carotene, which are all found in fruits and vegetables) may help to improve immune response and reduce the risk of illness.

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Immune deficiencies arise when one or more of the parts of the immune system are missing or not working correctly, leaving the body less able to fight disease-causing agents. There are two types of these deficiencies: primary, or inherited, immune deficiencies and secondary, or acquired, immune deficiencies.

The immune system has many parts that work together to protect the body from foreign invaders, such as microorganisms* and toxins*. When any segment of the immune system is absent or breaks down, it can lead to an immune deficiency. With so many elements of the immune system, there are more than 80 different types of primary immune deficiencies. They range from those that have severe and sometimes fatal effects to mild diseases that cause people few, if any, problems. About half a million people in the United States have some type of primary immune deficiency, with more boys than girls affected by these conditions.

Secondary immune deficiencies are much more common than inherited deficiencies. Unlike patients with primary immune deficiencies, people with secondary immune deficiencies are born with a healthy immune system, but sometime later in life the system becomes weakened or damaged. Both primary and secondary deficiencies typically lead to frequent infections and sometimes to additional medical problems, including certain cancers. These people often experience a variety of skin, respiratory, and bone problems as well, and they are more likely to have autoimmune diseases*.

The immune system consists of a group of organs, cells, and a specialized system called the lymphatic (lim-FAH-tik) system that helps clear infectious agents from the body. Together, they guard the body against infectious diseases. The lymphatic system is a key part of the immune system: it consists of lymphatic vessels, lymph nodes*, and the thymus (THY-mus) and spleen. Lymph nodes and lymphatic vessels transport lymph, a clear fluid that contains white blood cells called lymphocytes (LIM-fo-sites), throughout the body. The lymphocytes mature in the thymus, a gland located behind the breastbone. The spleen, an organ that is the center of certain immune system activities, is found in the upper-left side of the abdomen. Lymphatic tissue also is found in other locations throughout the body, including the tonsils* and the appendix*.

(ah-PEN-diks) is thenarrow, finger-shaped organ that branches off the part of the large intestine in the lower right side of the abdomen. Although the organ is not known to have any vital function, the tissue of the appendix is populated by cells of the immune system.

When a foreign substance or microorganism enters the body, phagocytes (FAH-go-sites) often are the first cells on the scene. These large scavenger white blood cells patrol the bloodstream, looking for possible invaders. When they find one, they engulf, digest, and destroy the intruder.

Other components of the immune response react when presented with specific antigens*. The most important players in this fight are two types of lymphocytes that learn to “recognize” and destroy the foreign invaders.

(AN-tih-jenz) are substances that are recognized as a threat by the body’s immune system, which triggers the formation of specific antibodies against the substances.

B cells, the first type, are white blood cells that produce antibodies*, which circulate in the blood and lymph streams. The first time B cells encounter a new foreign substance, they make antibodies in response to the intruder’s antigens. When the antibodies come across that specific antigen again, they attach themselves to it, marking it (and with it, the entire foreign substance or microorganism) for destruction by other cells. Antibodies also summon phagocytes and body chemicals, such as complement proteins*, to the site of an infection and move them into action against the antigens.

are proteins that circulate in the blood and play a role in the immune system’s response to infections. More than 20 complement proteins have been identified.

T cells, the second type, are specialized white blood cells that have several roles. They monitor and coordinate the entire immune response, which includes recruiting many different cells to take part in that response. Some T cells, the T helper cells, signal the B cells to start making antibodies. Other T cells, the T killer cells, attack and destroy substances that they recognize as foreign. Once the foreign antigens have been defeated, cleanup crews of scavenger phagocytes called neutrophils (NU-tro-fils), a type of white blood cell that can surround and destroy invading organisms, and macrophages (MAH-kro-fay-jez), another form of engulf-and-destroy cell, arrive to clear up remains of the infection.

A genetic* abnormality in any type of cell of the immune system can lead to a primary immune deficiency. Some of these deficiencies produce no symptoms, whereas others cause severe symptoms and may even be fatal. Although primary immune deficiencies are present at birth, some patients do not begin to show signs of the condition until later in childhood or even beyond childhood.

(juh-NEH-tik) refers to heredity and the ways in which genes control the development and maintenance of organisms.

There are several well-known primary immune deficiencies. About 1 person in 600 is born with selective IgA deficiency, a mild disease that most often affects those of European ancestry. People with this condition lack immunoglobulin (ih-myoo-no-GLAH-byoo-lin) A (IgA), a class of antibodies that fight organisms that can infect the mucous membranes that line the mouth, airways, and digestive system*. Many patients with this disorder experience few symptoms, but some may have frequent infections.

is the system that processes food. It includes the mouth, esophagus, stomach, intestines, colon, rectum, and other organs involved in digestion, including the liver and pancreas.

The SCID Mouse

To gain a better understanding of the human immune system, scientists developed a laboratory mouse that lacks an enzyme* necessary for its immune system to function properly. Like people with severe combined immunodeficiency disease, these “SCID” mice cannot fight infections.

(EN-zime) is a protein that helps speed up a chemical reaction in the body.

Another very useful mouse model was developed in the 1980s, when scientists transplanted parts of the human immune system into the mouse. This gave an opportunity to researchers to study the workings of the human immune response more easily, as well as the impact of drugs and viruses on the immune system. This mouse has been described as a “living test tube.”

The effects of common variable immunodeficiency, also known as hypogammaglobulinemia (hi-po-gah-muh-gloh-byoo-lih-NEE-me-uh), can range from mild to severe. Its symptoms occasionally affect infants but often do not appear until early adulthood. Those symptoms include frequent bacterial infections of the ears, sinuses*, bronchi*, or lungs brought on by low levels of various immunoglobulins, including IgA and IgG.

(BRONG-kye) are the larger tube-like airways that carry air in and out of the lungs.

Caused by defective genes on the X chromosome*, X-linked agammaglobulinemia (a-gah-muh-gloh-byoo-lih-NEE-me-uh) is uncommon and affects only males. Patients have very low levels of mature B cells as well as low levels of immunoglobulins, which can result in pus* collections in the lungs, sinuses, and ears in addition to other infections.

is a thick, creamy fluid, usually yellow or greenish in color, that forms at the site of an infection. Pus contains infection-fighting white cells and other substances.

Severe combined immunodeficiency (ih-myoo-no-dih-FIH-shen-see), also known as SCID or the “bubble boy” disease, strikes about 1 in a million people. This group of immune disorders is marked by major deficiencies in B cells and T cells, low levels of white blood cells, and decreased levels of IgA, IgG, and IgM antibodies. Such massive defects in the immune system can leave patients open to many serious infections, including pneumonia*, sepsis*, and meningitis*, which can lead to death.

(meh-nin-JY-tis) is an inflammation of the meninges, the membranes that surround the brain and the spinal cord. Meningitis is most often caused by infection with a virus or a bacterium.

Organisms that typically do not cause problems in a person with a healthy immune system may produce an “opportunistic infection” in a person with an immune deficiency. A person particularly at risk for such infections might be placed in isolation in a sterile environment. Custom Medical Stock Photo, Inc.

Other primary immune deficiency diseases may involve other components of the immune system, including neutrophils and phagocytes. There may be fewer of these cells produced, as occurs in a condition known as neutropenia (nu-tro-PEE-nee-uh) that is marked by low levels of neutrophils in the blood. Chronic* granulomatous (gran-yoo-LO-muhtus) disease is an immune disorder in which bacteria-fighting phagocytes are present but do not work properly. Genetic defects also can impair the complement system, a series of 20 or more proteins that come together during the body’s immune response to “complement,” or support, the work of antibodies. These conditions and defects in other parts of the complex immune system cause problems with the body’s immune response, often making a person more susceptible to a variety of infections.

Secondary immune deficiencies are acquired, rather than inherited, disorders. Many chronic conditions, such as diabetes*, cancer, and cirrhosis* of the liver, make a person more likely to have infections. Patients who have had their spleens removed or whose spleens do not work properly, as occurs in sickle-cell disease*, for example, are especially vulnerable to infection by certain bacteria that the spleen normally fights. In addition, some medications, particularly corticosteroids* and drugs used to treat cancer, may limit the immune system. Malnutrition, especially when there is a lack of protein in the diet, also may weaken a person’s immune response.

(dye-uh-BEE-teez) is a condition in which the body’s pancreas does not produce enough insulin or the body cannot use the insulin it makes effectively, resulting in increased levels of sugar in the blood. This can lead to increased urination, dehydration, weight loss, weakness, and a number of other symptoms and complications related to chemical imbalances within the body.

(kor-tih-ko-STIR-oyds) are chemical substances made by the adrenal glands that have several functions in the body, including maintaining blood pressure during stress and controlling inflammation. They can also be given to people as medication to treat certain illnesses.

The human immunodeficiency virus (HIV), a virus that attacks the immune system and is the cause of acquired immunodeficiency syndrome (AIDS), is responsible for a sharp increase in the number of people with secondary immune deficiencies. HIV destroys T cells, which are crucial to the normal functioning of the human immune system. This can lead to overwhelming infections. People can contract the virus through contact with blood, semen*, vaginal* secretions, and breast milk.

Immune deficiencies may be characterized by frequent, recurrent, or prolonged infections. In some cases, there may be an overwhelming or unusual infection. In others, organisms that typically do not cause problems in a person with a healthy immune system may produce an opportunistic infection* in a person with an immune deficiency. These infections are seen in people infected with HIV and often mark the onset of AIDS.

are infections caused by infectious agents that usually do not produce disease in people with healthy immune systems but can cause widespread and severe illness in patients with weak or faulty immune systems.

Although symptoms of opportunistic infections may suggest an immune deficiency, laboratory tests are needed to diagnose the specific deficiency. These include blood tests to measure levels of white blood cells, red blood cells, and platelets* and to measure the presence of specific types of cells, such as B cells and T cells. Other blood tests can measure the levels or function of antibodies (such as IgA, IgG, and IgM) and complement proteins. Skin tests may be done to check the responses of T cells. Other, more specific tests of the immune system’s competency depend on the type of deficiency suspected.

The primary goal of treating immune deficiencies is to prevent infections. Although it is a good idea for some people who have immune deficiencies to avoid contact with people who have infections, this is not always practical. Many patients take daily medication to prevent certain infections, and patients with antibody deficiencies may receive regular doses of the immunoglobulins they lack. People who have HIV or AIDS take combinations of drugs to keep the virus from making more copies of itself and destroying more T cells. Bone marrow* transplantation, to replace the absent or poorly functioning immune system cells of the affected person, is necessary for some patients with severe immune deficiencies, such as SCID. Prompt recognition and treatment of infections, including opportunistic infections, is essential.

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immune system

immune system System by which the body defends itself against disease. It involves many kinds of leucocytes (white blood cells) in the blood, lymph and bone marrow. Some of the cells (B-cells) make antibodies against invading microbes and other foreign bodies (antigens), or neutralize toxins produced by pathogens, while other antibodies encourage two types of leucocytes, phagocytes and macrophages, to attack and digest invaders. T-cells also provide a variety of functions in the immune system. See also interferon

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immune system

immune system Series of defence mechanisms of the body. There are two major parts: humoral, mediated through antibodies secreted into the circulation (immunoglobulins); and cell‐mediated. Lymphocytes produce antibodies against, and bind to, the antigens of foreign cells, leading to death of the invading organisms; other white blood cells are phagocytic and engulf the invading organisms.

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